The lymphatic system is crucial for the maintainance of good health and for the prevention and cure of disease. Congenital hypoplasia and failed regeneration of lymphatic tissue result in lymphedema. Primary lymphedema appears at birth (Milroy disease) or, more commonly, after puberty (Meige disease). Although lymphedema was first described more than a century ago, only recently some progress has been made in understanding the mechanisms that cause it and in the identification of the players that participate in the normal development of the lymphatic vasculature. Research in the area of developmental lymphangiogenesis has been hindered by the lack of known lymphatic-specific markers. Consequently, hypotheses about the origin of lymphatic endothelial cell precursors, and the cellular and molecular mechanisms regulating the formation of the lymphatic vasculature are still controversial. This grant proposal is based in our identification of the homeobox gene Proxl as the first specific marker of lymphatic endothelial cells. Functional inactivation of Proxl in mice results in the complete absence of the lymphatic vasculature. Detailed analyses of obese Proxl heterozygous mice demonstrated that the abnormal accumulation of fat observed in these mice is the consequence of lymphatic vascular leakage, a result indicating that lymphangiogenesis requires constant Proxl activity. A better understanding of sources of lymphatic endothelial cells during developmental and postnatal lymphangiogenesis and the elucidation of the cellular and molecular mechanisms by which Proxl participates in the formation of the lymphatic vasculature will increase our understanding of normal lymphangiogenesis, and therefore, advance the treatment and prevention of disorders of the lymphatic system.